Clinical and genomic distinction of class 1/2/3 <i>BRAF</i>-mutant colorectal cancer and differential prognosis.
Authors: Yungchang Chen, Yanhong Deng, Yutong Ma, He Huang, Yang Liu, Yaru Zhang, Hongyu Zhang, Sheng Ye, Hongqiang Guo, Mengmeng Wu, Xingxiang Pu, Xinggui Chen, Chaoyong Liang, Qiuxiang Ou, Xue Wu, Yang Shao, Tongyu Lin
Journal: Journal of Clinical Oncology (2022)

3533 Background: Mutations occurring at the V600 amino acid of BRAF is the most common BRAF mutations in colorectal cancer (CRC), which lead to RAS-independent active monomers (Class 1) and are the targets of BRAF inhibitors. BRAF non-V600 mutants can be further classified as RAS-independent active dimers (Class 2) and RAS-dependent impaired kinase (Class 3). The clinical and genetic distinction of CRC patients carrying different subtypes of BRAF mutations remain to be revealed. Methods: A multicenter retrospective study investigated the mutational profiles of 2,118 CRC patients whose baseline tumor samples were analyzed between June 2015 and June 2020 using capture-based hybrid NGS targeting 400+ cancer-related genes. Clinical characteristics including age, sex, stage, and tumor location were analyzed. A public cBioPortal cohort of 471 metastatic CRC patients was used for survival analysis. Results: A total of 473 patients were identified to contain BRAF mutations and can be sub-grouped into Class 1 (N = 246), Class 2 (N = 29), Class 3 (N = 53), and others (N = 145). All Class 1 BRAF mutations were V600E, while the Class 2 and Class 3 mutations were predominantly G469 (52%) and D594 (56%), respectively. No difference in patient’s age, sex, and stage was observed among BRAF Class 1-3 subgroups, but the anatomical location of the tumor differed among subgroups, particularly between Class 1 and Class 3 BRAF-mutant patients significantly (p = 0.027). Specifically, 39% of tumors carrying Class 1 mutations occurred at the right colon, while the most frequent location of tumors with Class 3 mutations was rectum (58%). Mutational profiling revealed that KRAS and APC mutations were enriched in Class 2/3 compared to Class 1 BRAF-mutant patients, while RNF43 and SMAD4 mutations were more frequently observed in Class 1 patients. Mutations causing the activation of the Wnt or RTK/RAS signaling pathways were also more common in Class 2/3 subgroups comparing to Class 1 patients. Furthermore, based on the analysis of mutation allele frequency, Class 1 BRAF mutations tended to be drivers while Class 2/3 BRAF mutations were more likely to be passengers. In addition, mutational signature profiling showed that the NER signature was enriched in Class 1 BRAF-mutant patients but the APOBEC signature in Class2/3 classes. The tumor mutational burden of Class 2 BRAF tumors was higher than the other two subgroups (median: 10.4 vs 7.6 and 8.4), and microsatellite instability-high tumors were more common in Class 1 (11% vs 7% and 4%). In the cBioPortal cohort, Class 1 BRAF-mutant patients had the worst overall survival whereas Class 3 patients demonstrated the best prognosis. Conclusions: The clinical and genetic features of CRC patients harboring Class 2 and 3 BRAF mutations were different from those carrying Class 1 BRAF mutations in aspects including tumor location, concurrent mutations, mutational signatures, as well as survival outcomes.